A phase I/II study of the protease inhibitor ritonavir in children with human immunodeficiency virus infection.
BACKGROUND
Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human immunodeficiency virus (HIV) infection. In a phase I/II study, we assessed the safety, tolerability, and pharmacokinetic profile of the oral solution of ritonavir in HIV-infected children and studied the preliminary antiviral and clinical effects.


METHODS
HIV-infected children between 6 months and 18 years of age were eligible. Four dose levels of ritonavir oral solution (250, 300, 350, and 400 mg/m given every 12 hours) were evaluated in two age groups (</=2 years, >2 years). Ritonavir was administered alone for the first 12 weeks and then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks.


RESULTS
A total of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) were included in this analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in discontinuation of ritonavir in 7 children. Ritonavir was well absorbed at all dose levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cells counts increased by a median of 79 cells/mm3 after 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 to 2 log10 copies/mL within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/m for the 24-week period.


CONCLUSIONS
The oral solution of ritonavir has potent antiretroviral activity as a single agent and is relatively well tolerated by children when administered alone or in combination with zidovudine or didanosine.
Mueller
B U
BU
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA.
Nelson
R P
RP
Sleasman
J
J
Zuckerman
J
J
Heath-Chiozzi
M
M
Steinberg
S M
SM
Balis
F M
FM
Brouwers
P
P
Hsu
A
A
Saulis
R
R
Sei
S
S
Wood
L V
LV
Zeichner
S
S
Katz
T T
TT
Higham
C
C
Aker
D
D
Edgerly
M
M
Jarosinski
P
P
Serchuck
L
L
Whitcup
S M
SM
Pizzuti
D
D
Pizzo
P A
PA
D000284:Administration, Oral; D000293:Adolescent; D019380:Anti-HIV Agents / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D016049:Didanosine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D008297:Male; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019562:Viral Load; D015215:Zidovudine / Q000627:therapeutic use
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D015215:Zidovudine; D016049:Didanosine; D019438:Ritonavir